Opiod antagonists have been indispensable as tools in opioid research. For example, the chief criterion for the classification of an agonist effect as being opioid receptor mediated is the ability of known opioid antagonists naloxone or naltrexone to reversibly antagonize this effect in a competitive fashion. The usefulness of naloxone and naltrexone for this purpose stems from the fact that they are universal opioid antagonists; that is, they are capable of antagonizing the agonist effects mediated by multiple opioid receptor types.
Since it is now firmly established that there are a minimum of three opioid receptor types (.mu., .kappa. and .delta.), it has become increasingly evident that selective opioid antagonists are valuable pharmacological tools for identifying receptor types involved in the interaction with opioid agonists. One of the major advantages of selective opioid antagonists over selective agonists is their utility in probing the interaction of endogenous opioid peptides and new opioid agonists with opioid receptor types. Moreover, since it is sometimes not easy to distinguish among .mu., .kappa. and .delta. opioid receptor mediated agonist effects if the pharmacological endpoints are identical (e.g. antinociception or inhibition of a smooth muscle preparation by agonists), selective antagonists clearly have wider utility as tools than selective agonists.
The general utility of selective antagonists as pharmacological tools depends upon the correlation of in vitro and in vivo acitivity. This can be accomplished more easily with non-peptide ligands because they generally can penetrate the blood-brain barrier and therefore can be administered peripherally in vivo. Also, they are less subject to metabolism than are peptides.
In addition to their uses as pharmacological tools, selective, non-peptide opioid antagonists have been described as having potential clinical applications in the treatment of a variety of disorders where endogenous opioids play a modulatory role. These include for instance disorders of food intake, shock, constipation, mental disorders, CNS injury, alcoholism, and immune function (immune stimulation or suppression) (P. S. Portoghese et al., J. Med. Chem., Vol 34: 1757-1762, 1991).
Non-peptide, competitive, .delta.-selective opioid antagonists have been found recently. The prototypes are: cyprodime for .mu. (H. Schmidhammer et al., J. Med. Chem., Vol. 32:418-421, 1989; H. Schmidhammer et al., J. Med. Chem., Vol. 33: 1200-1206, 1990), norbinaltorphimine for .kappa. (P. S. Portoghese et al., J. Med. Chem., Vol. 30:238-239, 1987), and naltrindole for .delta. opioid receptors (P. S. Portoghese et al., J. Med. Chem., Vol. 31:281-282, 1988).
These compounds (cyprodime, norbinaltorphinine and naltrindole) are being used as pharmacological tools. They have been tritium labelled and can be used as receptor selective ligands in opioid receptor binding studies to sort out the affinities of new ligands to different receptors and to determine whether a compound is selective to a special receptor.
An object of the present invention was to find new, highly selective .delta. opioid receptor antagonists with high potency. Another object was to find highly selective .delta. opioid receptor antagonists with high immunosuppressive potency. The high selectivity for .delta. opioid receptors would repress adverse side effects caused by the interaction with other receptors. Still another object was to find compounds which have a brain-cell protecting effect. The problem with the .delta. opiod receptor antagonists known from the prior art is that they are not highly selective.